Bacterial efflux pumps can cause multidrug resistance when overexpressed, and mutational mechanisms of overexpression have involved an array of global regulators. In Staphylococcus aureus pumps NorA, NorB, and NorC can confer resistance to various quinolone antimicrobials along with chloramphenicol and some dyes. Pump Tet38 confers resistance to tetracyclines, and pump AbcA confers resistance to plactams with hydrophobic side-chains. Two global transcriptional regulators, MgrA and NorG, are known to have direct regulatory roles in the expression of various of these pumps. The work described below has focused on i) defining the regulatory mechanisms that control pump expression (including the complex interactions of various regulators), ii) determination of the role of pump expression in the adaptation of S. aureus to survival in an abscess, its most common cause of infection, iii) determination of the environmental signals that trigger pump expression, and iv) defining the natural substrates of these generally broad-spectrum pumps, for which antimicrobials may be incidental substrates.